Using a rsFC analysis, we placed seed in the cingulate gyrus (3 ant, 3 post, 1 middle division) in a group of smokers. Acute nicotine, compared to placebo, increased 7 specific cingulate-cortical circuits consistent with behavioral characteristics of smoking. The connectivity strength of a circuit from the dACC to the ventral striatum (VS) was inversely correlated with addiction severity (FTND), but not altered by acute nicotine, suggesting in this double dissociation the existence of brain circuits that indexed cognition vs. addiction. The nAChR &#945;5 subunit gene functional variant rs16969968 associated with a virtually identical dACC-VS/EA rsFC, such that the risk allele leads to reduced rsFC in the circuit;rsFC strength was reduced in smokers compared to nonsmokers;reduction of rsFC predicts more severe nicotine addiction. Multiple brain regions were identified with reduced white matter integrity (fractional anisotropy, FA) in schizophrenia and in smoking independently. The only overlapping FA reduction between the two conditions was in the left anterior thalamic radiation/anterior limb of the internal capsule, a fiber track that connects frontal cortex (including dACC) to striatum. Reduced rsFC strength in the same circuit was found in patients with psychiatric conditions that was independently and additively present with the nAChR &#945;5 genetic effect. These resting state and DTI data provide converging evidence that this circuit may be related to high risk of smoking in psychiatric conditions. The above findings do not speak to the behavioral significance of anatomical and rsFC abnormalities. Striatal-cingulate regions identified are implicated in response inhibition (RI)/impulsivity processing. A GO/NOGO task indicated striatum and dACC activation and a significant group effect iin dACC. The striatal RI response is positively associated with FTND and negatively associated with rsFC strength between dACC-VS, indicating that rsFC may be indexing a RI function such that a reduced rsFC in the circuit is related to less controlled striatal activity during inhibitory functioning;the striatal response itself appears linked to nicotine addiction severity. This multi-modal imaging approach implicates a dACC-VS/EA circuit in smoking, and that this circuit can tie together aspects of the genetic, behavioral, comorbidity and cognitive correlates of smoking to provide a particularly salient biomarker for guiding and testing new treatment development. Anatomical differences and network characteristics underlying smoking cue reactivity. A distributed network of brain regions is linked to drug-related cue responding. However, the relationships between smoking cue-induced phasic activity and possible underlying differences in brain structure, tonic neuronal activity and connectivity between these brain areas are as yet unclear. Six brain areas, dorsal lateral prefrontal cortex (dlPFC), dorsal medial prefrontal cortex (dmPFC), dACC, rACC, occipital cortex, and insula/operculum, showed smoking cue-elicited activity in smokers compared with controls. Secondary analysis showed that rsFC strength between rACC and dlPFC was positively correlated with cue-elicited activity in dlPFC;rsFC strength between dlPFC and dmPFC was positively correlated with the cue-elicited activity in dmPFC;rsFC between dmPFC and insula/operculum was negatively correlated with the cue-elicited activity in both dmPFC and insula/operculum, suggesting these brain circuits may facilitate the response to salient smoking cues. The gray matter density in dlPFC was decreased in smokers and correlated with cue-elicited activity in the same brain area, suggesting a neurobiological mechanism for the impaired cognitive control associated with drug use. These results begin to address the underlying neurobiology of smoking cue salience, and may speak to novel treatment strategies and targets for therapeutic interventions. Factors underlying prefrontal and insula structural alterations in smokers. In a large, well-matched sample of smokers and non-smokers gray matter density was lower in PFC in high pack-years smokers and inversely related to pack-years. Insular cortex gray matter density was higher in smokers and associated with TAS total score and with difficulty-identifying-feelings factor. The most highly dependent smokers show lower PFC FA, which was negatively correlated with FTND. These data suggest chronic tobacco use is correlated with PFC gray matter damage, while differences in insula gray matter and PFC white matter appear to reflect stable and heritable differences between smokers and non-smokers. Nicotine and working memory (WM): The cognitive-enhancing properties of nicotine on WM remain unclear. We explored the impact of transdermal nicotine on neural functioning in minimally-deprived smokers and differences between smokers and nonsmokers using a mixed block/event-related fMRI design that attempted to isolate specific central executive operations within WM function. Across both groups, task-blocks were associated with bilateral activation, notably in m/lPFC, ant insula, and parietal regions, whereas individual attentional-switch trials were associated with activation in a similar, but predominantly left-lateralized network. Within the smoker group, although nicotine increased heart rate, altered performance and mood, and reduced tobacco cravings, no acute drug (state-like) effect on brain activity was detected for either the task or switch effects. However, relative to nonsmokers, smokers showed greater tonic activation in medial superior frontal cortex, right ant insula, and bilateral anterior PFC throughout task blocks (trait-like effect), suggesting smokers require recruitment of additional WM-control and supervisory control operations during task performance. Neurocognitive effects of Varenicline and nicotine: Varenicline, is a nicotinic acetylcholine receptor partial agonist, is an efficacious pharmacotherapy for smoking cessation treatment. We are examining an array of cognitive, affective, and reward processing tasks to explore the effects of smoking abstinence, transdermal nicotine, and varenicline administration on brain function and behavioral performance. Initial results from one task suggest vareniclines efficacy as a smoking cessation aid may partly lie in its ability to decrease amygdala reactivity to emotionally evocative stimuli and amygdala-insula rsFC, which may ameliorate the negative consequences of nicotine withdrawal and thus drug seeking behavior. In the absence of nicotine, varenicline reduced amygdala reactivity. In the presence of nicotine, reactivity was also reduced, but did not differ as a function of pill. Using task-defined amygdala seed regions identify from the above analysis, indicated amygdala-insula rsFC was reduced in the nicotine, relative to placebo condition;in the absence of nicotine, such connectivity was also reduced by varenicline. Nicotine and information processing. The impact of nicotine on all aspects of information processing has not been well delineated. We sought to determine the relative behavioral and functional effects of nicotine on dissociable aspects of information processing (i.e., selective attention and motor intention). Smokers were overall more accurate than controls, while nicotine significantly increased the response to intentional primes in brain regions known to mediate response readiness, e.g., inferior parietal lobe, supramarginal gyrus, and striatum. These data suggest that the behavioral effects of nicotine in smokers are not limited to information processing input (i.e., selective attention) but are generalizable to output functions (i.e., motor intention). Nicotine's effects on intention appear to be mediated by a facilitation of function in brain regions associated with in